The overall goal of this proposal is to contribute to the understanding of how HIV-1 infected target cells influence NK cell phenotype, activation state, and viability. HIV-1 infected targets may influence NK cells in several ways; including HIV-1 envelope interactions with chemokine receptors expressed on activated NK cells and their relation to HIV-1 induced modulation of cytokine expression during HIV-1 disease. In the first aim, we propose to analyze NKs by incubating PBMCs with autologous CD4+ primary T cells infected with HIV-1 in vitro and testing for virus-induced modulation of NK activation state, viability, and proliferative capacity. We will evaluate NK activation by CD107a exposure upon target cell interaction and characterize proinflammatory and apoptosis related gene expression by RNase protection assays. In the second aim, we will investigate the accessory role of dendritic cells in NK recognition and killing of HIV-1 infected target cells, in order to test the general hypothesis that NK cells are impaired in their ability to lyse HIV-infected targets in the absence of accessory cell help. Overall, this research will improve our understanding of mechanisms of control of HIV and potentially identify new targets for intervention. [unreadable] [unreadable]